This invention relates to treatment of human neurologic damage, and in particular to a method for increased regeneration and repair of damaged neurons and nerve axon myelin coatings, and nerve cell repair.
Demyelination occurs when the myelin coating around nerve axons degenerates resulting in a defect in the ability to transmit nerve impulses. For example, multiple sclerosis is a disease of unknown cause in which degeneration occurs in the myelin sheath surrounding the nerves. This demyelination is also found in many other diseases such as transverse myelitis. Demyelination also occurs after trauma to the brain or spinal cord, after a stroke, in neurodegenerative diseases such as amyotropic lateral sclerosis and Alzheimer""s disease, as well as in viral diseases including AIDS.
A cell type in the nervous system called the oligodendroglia is intimately involved in myelin regeneration, repair and maintenance of the nerve cells. Repair occurs by the repetitive wrapping of the plasma membranes of the oligodendroglia cells around damaged nerve cells and offers continuing metabolic nerve cell support. In the art, it has been established that for 0-2A progenitor cells that produce oligodendroglia cells proliferation is induced in culture by type-1 astrocytes. A recognized mitogen for 0-2A progenitor cells is platelet-derived growth factor (PDGF), and PDGF is a potent mitogen for 0-2A progenitor cells in vitro. Thus, laboratory experimentation has suggested that PDGF is crucial for the control of nerve cell repair and myelination in the nervous system.
It is also known in the art that the development of oligodendrocytes from precursor cells also includes an effector component which depends on thyroid hormone that stops cell division and initiates differentiation at the appropriate time.
Further, it is also known in the art that proteins generally referred to as thrombopoietins support biological activity that ultimately results in the production of platelets and other cells from the myeloid line, including markedly increasing PDGF production. Methods of preparation of thrombopoietin are disclosed in recent patents, for example, U.S. Pat. No. 5,795,569 issued to Amgen, Inc. and processes for producing them by recombinant genetic engineering techniques are also disclosed. Hence, the availability of thrombopoietins in pharmaceutically available quantities is to be expected in the near future.
A method of treatment of degenerative neurologic diseases provides for the administration of therapeutically effective amounts of an enhancement agent, such as thrombopoietin, to enhance the regeneration of neuron cells. A regulatory agent, such as thyroid hormone or thyrotropin, may also be included as a regulator of cell division and differentiation. The method may be used with humans and also with other mammals with neurologic damage.
The thrombopoietin may be orally ingested by the patient, or may be administered by intravenous, intramuscular or intrathecal injection.
The method can further include the step of administering thyroid hormone to the patient. The thyroid hormone may be orally ingested by the patient, or may be administered by intravenous, intramuscular or intrathecal injection. The thyroid hormone may include thyroid hormone extract or synthetic thyroid hormone.
The method can also further include the step of stimulating human thyroid production by administering thyrotropin to the patient. The thyrotropin may be orally ingested by the patient, or may be administered by intravenous, intramuscular or intrathecal injection.
The thrombopoietin may be isolated from a mammal, made by recombinant means, or made by synthetic means. It may be human thrombopoietin, a fragment of human thrombopoietin, or a variant polypeptide of human thrombopoietin. The therapeutically effective amount of thrombopoietin ranges from about 1.0 to about 100 xcexcg/kg body weight per day.
In the method of this invention, the thyroid hormone can be co-administered to the patient with the thrombopoietin. In an alternative method, the thyrotropin can be co-administered to the patient with the thrombopoietin.
The invention further consists of a pharmaceutical composition for treatment of neurologic damage in a mammal, comprising thrombopoietin and thyroid hormone. The composition can contain between about 0.07 to about 10 mg of thrombopoietin per dose unit. The composition may be formulated such that it contains between about one and about three times as much thyroid hormone as thrombopoietin. In this composition, the thrombopoietin may be isolated from a mammal, made by recombinant means, or made by synthetic means. The thrombopoietin may be human thrombopoietin, a fragment of human thrombopoietin, or a variant polypeptide of human thrombopoietin. The thyroid hormone may be thyroid hormone extract or synthetic thyroid hormone.
The invention further consists of a pharmaceutical composition for treatment of neurologic damage in a mammal, comprising thrombopoietin and thyrotropin. The composition can contain between about 0.07 to about 800 mg of thrombopoietin per dose unit. In this composition, the thrombopoietin may be isolated from a mammal, made by recombinant means, or made by synthetic means. The thrombopoietin may be human thrombopoietin, a fragment of human thrombopoietin, or a variant polypeptide of human thrombopoietin.
A primary object of the present invention is to provide a method and formulation for neuron or myelin regeneration and maintenance in the nervous system.
Another object of the present invention is to provide a method for neuron and myelin regeneration and maintenance using endogenous platelet-derived growth factor (PDGF), production of which is induced by use of an enhancement agent.
Another object of the present invention is to increase PDGF production by administration of a therapeutically effective amount of thrombopoietin (TPO).
Another object of the invention is to provide a regulatory agent which effects a decrease in the rate of cellular division of oligodendrocytes and initiates differentiation into functional neuronal support cells.
Another object of the invention is to provide a method for treatment of neurological disorders including administration of TPO and co-administration or sequential administration of a regulatory agent, such as thyroid hormone, thyrotropin or the like.
Other objects, advantages and novel features, and further scope of applicability of the present invention will be set forth in part in the detailed description to follow, and in part will become apparent to those skilled in the art upon examination of the following, or may be learned by practice of the invention. The objects and advantages of the invention may be realized and attained by means of the instrumentalities and combinations particularly pointed out in the appended claims.